This grant proposes to develop novel conjugated opioid peptide drugs that are metabolically stable, readily cross the blood-brain barrier and possess high analgesic efficacy with minimal side-effects. Protein Delivery Inc. has developed a novel technology that permits the transport of peptides into the CNS, and protects them from enzymatic metabolism. This amphophilic oligomer conjugation technology has been applied to endogenous enkephalin peptides. Preliminary experiments demonstrated that following intravenous administration, conjugated enkephalins produced potent, long-lasting analgesia in the rat hot-plate test. In contrast, unconjugated enkephalin had no analgesic activity, even when tested at a 20-fold higher dose. In vitro studies demonstrate that conjugated enkephalin is remarkably stable when incubated with brain homogenates, exhibiting little degradation after 1 hour incubation, while unconjugated enkephalin is completely degraded within 15 minutes. Thus, the unique peptide conjugation technology has powerful implications for the development of novel analgesic therapies. We propose to study other conjugated opioid peptides, which act selectively on mu, delta and kappa opioid receptors in a range of analgesic tests. Ultimately, we intend to further develop this enabling technology to generate a new class of opioid peptide analgesic agents that are superior in their receptor selectivity and therapeutic indices, as well as their ability to treat conditions such as neuropathic pain. PROPOSED COMMERCIAL APPLICATIONS: Novel analgesic agents with a superior therapeutic index are needed for the treatment of chronic pain. Given the 34-50 million chronic pain sufferers in the US, the commercial opportunities and clinical needs are great The conjugated peptide technology facilitates transport across the blood brain barrier, and could be applied to many neuroactive peptides.